1. Field of the Invention
The present invention relates to methods for diagnosis and treatment of atrioventricular conduction blockage.
2. Description of the Prior Art
Proper functioning of the pathway through which impulses that govern the heart beat are transmitted is vital for any organism. In the mammalian heart the electrical component of each heart beat originates in the sinoatrial node (pacemaker) of the heart and must pass through the atrioventricular (A-V) node in order to reach the ventricles and elicit the contraction needed to pump blood.
The electrical components of a heart beat can be detected by an electrocardiogram (EKG) and appear as follows: first, an electrical impulse known as P-wave, which indicates the triggering of the sinoatrial node and activation of the atria, and second, a complex group of electrical impulses individually named Q-, R-, S-, and T-waves and collectively known as the ventricular complex, which indicates that the signal has passed the A-V node and that the ventricles are activated to contract. The Q-wave is sometime quite small and may not be visible; therefore, the interval between atrial and ventricular depolarization (Activation) is generally measured by the P-R interval. An EKG of a normal heart is shown in FIG. 1. Normally, both the interval between two P-waves (the time of a complete heart beat) and the interval between a P-wave and following R-wave are consistent from one heart beat to another. The normal R-R interval is about 0.2 second. However, when the transmission of a signal through the A-V node is impaired, there is an increase in the time delay from the P-wave to the R-wave. This can be seen in FIG. 8. Impaired functioning of the heart indicated by an increase in the P-R interval is known as first degree heart block. With increased impairment of A-V conduction, the time delay between the P-wave and the R-wave becomes longer. Eventually, the signal may fail to be transmitted at all, and some of the expected contractions of the ventricles will not occur, resulting in the condition known as second degree heart block. For example this condition occur when there are two atrial beats for each ventricular beat, known as 2:1 A-V block. Other relationship between beats in second degree heart block, such as 3:2 A-V block, are also possible, as shown in FIG. 9. If no A-V conduction occurs at all, the beating of the atria and ventricles becomes completely dissociated, and the ventricles beat at a much slower rate than normal, resulting in severely decreased efficiency of the heart as a pump. This dissociation is known as third degree heart block. Continued functioning of the heart in this mode may result in imminent death.
Several conditions of the heart are known to affect A-V node transmission. These includes ischemia (low blood flow to heart tissue) and hypoxia (low oxygen blood level) of the A-V node. Disorders that can cause hypoxia and ischemia include partial or complete obstruction of arteries leading to the heart and constriction of such arteries. Furthermore, it has been known that A-V node action potentials (electrical potential during activity of the node) are depressed by hypoxia and, concomitantly, the atria-to-His bundle conduction time is markedly increased. The His bundle is a small band of atypical cardiac muscle fibers that propagates the electrical signal from the atrial to the ventricular end of the A-V node. Additionally, stimulation of the vagus nerve, the parasympathetic nerve that controls heart beat, results in slowing of the heart beat and an increase in the P-R interval. The vagus nerve interacts with the heart by releasing acetylcholine, and, therefore, the presence of high levels of acetylcholine will also cause A-V conduction disturbances. Lastly, as easly as 1929 it was observed that adenosine, if injected in large amounts, can produce heart block. Adenosine is normally present in myocardial tissue, as well as in other tissues, but is normally present only in much lower concentrations than those that produce heart block. Adenosine and adenine nucleotides have been shown to produce dose-dependent A-V conduction block in guinea pig hearts. Adenosine is also known to depress Ca.sup.2+ -mediated action potentials in mammalian atria.
Presently, A-V node conduction blockage can be determined with certainty only from an electrocardiogram (EKG). If an EKG is not available, clinical techniques of heart beat monitoring by stethoscope or by taking of the pulse may give some indication of A-V node blockage, but with considerably less certainty.
Treatment of A-V conduction blockage is presently limited to administration of atropine and pacemakers. Atropine blocks the parasympathetic affect of the vagus nerve on the heart. Therefore, atropine is effective in treating A-V block caused by disorders of the vagus nerve. However, administration of atropine has not been effective in relieving A-V block in all cases for reasons that have previously been unknown. As shown in a 1968 clinical study only 10 of 20 patients with A-V block (second degree or complete), treated with atropine within 8 hours of the onset of symptoms of myocardial infarction, showed improved A-V conduction. No improvement was seen in the remaining 10 patients. Also, only 1 of 11 patients treated more than 8 hours after the onset of symptoms showed a favorable response to atropine. (Adgey et al, Lancet, 2, pp. 1097-1101 (1968)). Indeed, the administration of atropine in some instances has been observed to aggravate A-V node block.
Prior to investigations of one of the present inventors in the 1960's, there was no recognition that ischemia and hypoxia of the heart led to increased adenosine production in myocardial tissues. It was not until the three-way cause-and-effect relationship of hypoxia, adenosine production, and A-V node disturbance was recognized in the present invention that a rational treatment of A-V node conduction disturbances became possible. This novel treatment comprises the use of an adenosine antagonist to block the action of adenosine on the A-V node.
One class of adenosine antagonists, the group of compounds known as methylxanthines, are well known as reagents which relieve bronchial asthma. Methylxanthines are known to affect the heart but have not been used in cases of A-V node disturbances. In fact, many of the prior uses of methylxanthines in clinical situations are now contraindicated in conditions of hypoxia and ischemia. Methylxanthines are well known as stimulators of myocardial contraction (U.S. Pat. No. 3,928,609) and as dilators of coronary blood vessels (U.S. Pat. Nos. 4,153,696 and 3,989,833). Well known examples of methylxanthine are caffeine, which is 1,3,7-trimethylxanthine, and theophylline, which is 1,3-dimethylxanthine. The best known, clinically-used methylxanthine is aminophylline, the ethylenediamine derivative of theophylline. Several derivatives of theophylline have been proposed to be useful in treatment of tacharrhythmia (rapid heart beat; U.S. Pat. No. 4,144,340) and other unspecified arrhythmias (U.S. Pat. Nos. 3,962,243). These and other derivatives of theophylline act by releasing theophylline itself into the blood stream where they undergo hydrolysis (U.S. Pat. No. 4,085,214). However, past studies have shown that when theophylline was used to treat angina pectoris, the treatment resulted in increased heart rate and increased myocardial oxygen consumption (U.S. Pat. No. 3,896,127). In summary, methylxanthines have been used to stimulate heart contraction but in the process increase oxygen consumption, a condition that has detracted away from the use of methylxanthines in the treatment of conditions that may involve an ischemic heart.